The overall objective of the proposed research is to develop an orally active inhibitor of MPO as a treatment for acute and chronic diseases. MPO is an abundant enzyme in leukocytes and its expression can be induced in macrophages at inflammatory sites such as atherosclerotic lesions. MPO catalyzes a reaction between chloride and hydrogen peroxide to generate hypochlorous acid, a strong oxidizing agent. Multiple lines of evidence implicate MPO in the initiation and progression of atherosclerosis through oxidation of lipoproteins, impairment of reverse cholesterol transport, and reduction of bioavailable NO. A small molecule inhibitor of MPO may be an important component in a list of therapeutic options for the treatment of chronic inflammatory diseases including atherosclerosis. In Specific Aim 1 we propose to screen a small molecule library for inhibitors of MPO. In Specific Aim 2 we propose to test the small molecule inhibitors in a variety of secondary assays designed for selectivity and cellular function before testing the small molecule in an in vivo model of atherosclerosis. PUBLIC HEALTH RELEVANCE: Myeloperoxidase is recognized as an important causative contributory agent in inflammatory diseases including atherosclerosis. An inhibitor of myeloperoxidase would provide a novel therapeutic agent that could be used as an adjunct therapy to statins and other therapeutics already on the market. The experiments outlined in this Phase I SBIR application will help set the stage for the development of a novel and safe myeloperoxidase inhibitor.